Pjjperidine derivatives and preparation



PIPERIDINE DERIVATIVES AND PREPARATION THEREOF August Hans Lutz and Otto Schnitler, Basel, Switzerland, assignors to Hoflmann-La Roche Inc., Nutley, N. J., a corporation of New Jersey No Drawing. Application January 5, 1956 Serial No. 557,455

Claims priority, application Switzerland January 19 1955 2 Claims. (31. 260-2941 This invention" relates to novel chemical compounds and to novel processes for their preparation. More particularly, the invention relates to novel compounds having the formula O I R. a .4 R oa BOH-R o=o2 shH-R wherein:-

R and R each represents a, monovalent radical having not more than four carbon atoms. selected from the group consisting of alkyl and alkenyl radicals;

R represents a monovalent radical having not more than seven carbon atoms selected from theg'roup consisting of aryl hydrocarbon, aralkyl hydrocarbon, alkyl, a1 koxyalkyl and alkenyl radicals; and

R and R each represents a member selected from the group consisting of hydrogen and alkyl radicals having not more than three carbon atoms. The invention further. relates to a. novel process of making a compound of Formula I above which comprises condensing a compound having the formula (II) 0 a )k t i' O,=Q CH.

N 4.. wherein the symbols.R ,.R R and. R have the same meaning indicated above, with an organometal.compel-ind having the formula wherein:

R represents: a monovalent radical havingrnot more than sevencarbon atoms selected from the group consisting of aryl hydrocarbon, aralkyl hydrocarbon, al-kyl,'

alkoxyalkyl and alkenyl radicals; and Z represents a member: selected from the group consisting of lithium and magnesium halide, andhydrolyt ically decomposing the rnetal-containingicondensation product obtained. I The tetrahydropyridinedion'es" of Formula; Ir above, used as starting-material's, can be. made. by" methodswhicli have been disclosed prior to the instant invention: see for instance Festschrift Emil Barell (1936), page 195 et seq.; and prior copending application Serial No. 349,564, filed April 17. 1953. The organometal compounds containing the radical R referred to above, can also be made by known methods. Suitable organometal 2,853,490 Patented Sept. 23', 1958 "ice above, include solid and liquid materials,1which can be purified by'crystallization and distillation. The said novel compounds are soluble in the usual organic solvents, and certain of them are also easily soluble in water. The compounds of Formula I are useful as r'nedicinals, in consequence of their activity upon the central nervous system; inparticular, said compounds are useful as sedatives and anticonvulsants. v

A particularly preferred group among the novel conipounds of the invention are those members of the class designated by Formula I above wherein R represents a monocyclic hydrocarbon aryl radical; these possess marked anticonvulsant activity. The 3,3- dialkyl-6-phenyl- 2,4-dioxo-pipe'ridines included within Formula I above are especially preferred as anticonvulsants.

In instances where the starting material of formula II above is a compound wherein R represents hydrogen, it is advantageous to employ approximately two molar proportions of organometal compound per molar proportion of tetrahydropyridinedione starting material, inasmuch as one molar proportion of the organometal compound is bound by the secondary hydrogen atom attached to the nitrogen atom, and a second in'olat proportion is required for the desired condensation at the ethylenic linkage. p p

The invention is further disclosed in the following examples, which are illustrative but not limitative thereof.

Example 1 20 g. of lithium was reacted in 1800 ml. of absolute diethyl ether with 230 g. of bromobenzene in known manner to form phenyllithium'. 84 g; of2',4=dioxd=3,3'-dimethyl-tetrahydropyridine was dissolved in 1000 m1. of boiling benzene and added to the ethereal solution of phenyllithiu'm, while stirring, and the reaction mixture was then refluxed. The salts which precipitated were decomposed by adding 3 N aqueous hydrochloric acid solution to the reaction mixture. The resulting aqueous layer was separated and discarded. The solvents (benzene, ether) were driven off from the organic layer, and the residue was purified by recrystallization from aqueous methanol. The product thus obtained, 2,4 -d ioXo=3",3'-dimethyl-'6-phenylpiperidine, had M. P. 168'-169 Ga. and was difficultly soluble in water.

Example 2 sodium sulfate; the solvent was driven oft and the residue was distilled in vacuo. The product, 2",4-dioxo-'3,3- diethyl'-6-(4-methoxy-n-butyl)-piperidine,- b'oiled at 166 167 C./0. 04 mm., and me1tedat' 41-.5 G;

7 Example 3 12 g. of magnesium chips was reacted in 500 ml. of absolute diethyl ether with 5-0 g. of methyl bromide and the resulting solution was added, while stirring, to a solution of 30 g. of 2,4-dioxo-3,3-diethyl--methyl-tetrahydropyridine in 400 ml. of hot toluene. The reaction mixture was refluxed, then was made Congo acid with 3 N aqueous sulfuric acid solution. The organic layer was separated, Washed well with 100 cc. of 3 N aqueous NaOH solution, and dried; then the solvent was driven off. The residue was crystallized from a mixture of benzene and petroleum ether. The product, 2,4-dioxo-3,3-diethyl-5,6-dimethylpiperidine thus obtained melted at 707l C.

Example 4 Example 5 12 g. of magnesium chips was reacted in about 500 ml. of absolute diethyl ether with 50 g. of methyl bromide, and the resulting solution was mixed with a solution of 60 g. of 1-methyl-2,4-dioxo-3,3-diethyl-tetrahydropyridine in 400 ml. of benzene. The mixture was refluxed, and then was set Congo acid with 3 N aqueous sulfuric acid solution. The organic layer was separated, washed with dilute aqueous sodium hydroxide solution, the solvent was driven ofi and the residue was distilled in vacuo. The product, 1,6-dimethyl-2,4-dioxo-3,3-diethylpiperidine, was obtained as a material boiling at 143 C./ mm.

The following compound were prepared by procedures similar to those set forth above:

2,4-dioxo-3,3-di-n-propyl-6-rnethyl-piperidine, M. P. 970-98". C., from 2,4-dioxo-3,3-di-n-propyltetrahydropyridine and methylmagnesium bromide;

2,4-dioxo-3,3-diethy1-6-allyl-piperidine, M. P. 151- 152 C., from 2,4-dio-xo-3,3-diethyl-tetrahydropyridine and allylmagnesium bromide;

2,4-dioxo-3,3-diethyl-6-n-butyl-piperidine, M. P. 50- 51 C., from 2,4-dioxo-3,3-diethyl-tetrahydropyridine and n-butylmagnesium bromide;

2,4-dioxo-1-methyl-3,3-diethyl-6-isopropyl piperidine, B. P. 91 C./0.0l mm., from 2,4-dioxo-1-methyl-3,3- diethyltetrahydropyridine and isopro-pylmagnesium bromide;

2,4-dioxo-3,3-dimethyl-6-isopropyl-piperidine, M. P. 152153 C., from 2,4-dioxo-3,3-dirnethyl-tetrahydropyridine and isopropylmagnesium bromide;

2,4-dioxo-1-methyl-3,3-diethyl-6-phenyl-piperidine, B. P. 143 C./0.04 mm., from 2,4-dioxo-1-methyl-3,3-diethyltetrahydropyridine and phenylmagnesium bromide;

2,4-dioxo-3,3-diethyl-6-isopropyl-piperidine, M. P., 100 C., from 2,4-dioxo-3,3-diethyl-tetrahydropyridine and isopropylmagnesium bromide;

2,4 dioxo3,3-diethyl-6-benzyl piperidine, M. P. 129- 130 C., from 2,4-dioxo-3,3-diethyl-tetrahydropyridine and benzylmagnesium chloride;

2,4-dioxo-3,3-diethyl-6-methyl-piperidine, M. P. 92- 93 C., from 2,4-dioxo-3,3-diethyl-tetrahydropyridine and methylrnagnesium iodide;

2,4-dioXo-3,3,6-triethyl-piperidine, M. P. 7071 C., from 2,4-dioxo-3,3-diethyl-tetrahydropyridine and ethylmagnesium bromide;

2,4-dioxo-3,3-diethyl-6-phenyl-piperidine, M. P. 104 C., from 2,4-dioxo-3,3-diethyl-tetrahydropyridine and phenylmagnesium bromide;

2,4-dioxo-3,3-di-n-propyl-5,6-dimethyl-piperidine, M. P. 96 C., from 2,4-dioxo-3,3-di-n-propyl-5-methyl-tetrahydropyridine and methylmagnesium bromide.

We claim:

1. A process which comprises condensing a compound having the formula wherein R and R each represents a monovalent hydrocarbon radical having not more than four carbon atoms selected from the group consisting of alkyl and alkenyl radicals, and

R and R each represents a member selected from the group consisting of hydrogen and alkyl radicals having not more than three carbon atoms,

with an organometal compound having the formula wherein R represents a monovalent radical having not more than seven carbon atoms selected from the group consisting of aryl hydrocarbon, aralkyl hydrocarbon, alkyl, alkoxyalkyl and alkenyl radicals; and

Z represents a member selected from the group consisting of lithium and magnesium halide,

and hydrolytically decomposing the metal-containing condensation product obtained, thereby producing a compound having the formula wherein R R R R and R each has the same meaning indicated above.

2. A process of making 3,3-dialkyl-6-phenyl-2,4-dioxopiperidine, wherein each alkyl radical contains not more than four carbon atoms, which comprises condensing 2,4- dioxo 3,3-dialkyl-tetrahydropyridine, wherein each alkyl radical contains not more than four carbon atoms, with approximately two molar proportions of phenylmagnesium halide, and hydrolytically decomposing the magnesiumcontaining condensation product obtained.

References Cited in the file of this patent UNITED STATES PATENTS 2,525,231 Masset Oct. 10, 1950 2,680,116 Frick et al. June 1, 1954 OTHER REFERENCES Petrenko-Kritshenko: C. A., 18:1485.

Kharasch et al.: Grignard Reactions of Non-metallic Substances, page 1258.

Clarke et al.: Chemistry of Penicillin, Princeton University Press (1949), page 992, column 1. 

1. A PROCESS WHICH COMPRISES CONDENSING A COMPOUND HAVING THE FORMULA 